Zhou Shuxia, Zhou Hua, Walian Peter J, Jap Bing K
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.
Biochemistry. 2007 Mar 13;46(10):2553-63. doi: 10.1021/bi602509c. Epub 2007 Feb 14.
The gamma-secretase complex is an intramembrane aspartyl protease that cleaves its substrates along their transmembrane regions. Sequential proteolytic processing of amyloid precursor protein by beta- and gamma-secretase produces amyloid beta-peptides, which are the major components of amyloid plaques in the brains of Alzheimer's disease patients. The gamma-secretase complex is therefore believed to be critical in the pathogenesis of Alzheimer's disease. Here we review the range of factors found to affect the nature and degree of gamma-secretase complex activity; these include gamma-secretase complex assembly and activation, the integral regulatory subunit CD147, transient or weak binding partners, the levels of cholesterol and sphingolipids in cell membranes, and inflammatory cytokines. Integrated knowledge of the molecular mechanisms supporting the actions of these factors is expected to lead to a comprehensive understanding of the functional regulation of the gamma-secretase complex, and this, in turn, should facilitate the development of novel therapeutic strategies for the treatment of Alzheimer's disease.
γ-分泌酶复合物是一种跨膜天冬氨酸蛋白酶，它沿着底物的跨膜区域进行切割。淀粉样前体蛋白先后经β-和γ-分泌酶进行蛋白水解加工，产生β-淀粉样肽，这是阿尔茨海默病患者大脑中淀粉样斑块的主要成分。因此，γ-分泌酶复合物被认为在阿尔茨海默病的发病机制中起关键作用。在此，我们综述了已发现的影响γ-分泌酶复合物活性性质和程度的一系列因素；这些因素包括γ-分泌酶复合物的组装和激活、整合调节亚基CD147、瞬时或弱结合伴侣、细胞膜中胆固醇和鞘脂的水平以及炎性细胞因子。对支持这些因素作用的分子机制的综合了解，有望促成对γ-分泌酶复合物功能调节的全面认识，进而有助于开发治疗阿尔茨海默病的新型治疗策略。
